Health-related quality of life (HRQL) is defined as a psychological construct describing the subjectively experienced health status based on different components of health including physical state, psychological well-being, social relations and functional capacities. Assessment of HRQL has become steadily more essential in order to evaluate the costs and benefits of modern treatment modalities in patients with chronic and incurable diseases. This is particularly true for patients with home mechanical ventilation (HMV) and severe objective limitations in daily living. Modern instruments such as the Severe Respiratory Insufficiency (SRI) Questionnaire have been specifically designed for clinical trials which aim at assessing the effects of HMV on HRQL in these patients. Recent work has shown that mental health in clinically stable patients following establishment of HMV can be normal despite substantial physical handicaps. Further, HRQL has been shown to be predominantly influenced by the underlying disease. Accordingly, there is increasing evidence that HMV provides beneficial effects on HRQL in patients with neuromuscular and thoracic rib cage diseases, but in contrast, this remains still controversial in patients with COPD. Here, prospective controlled trials using modern specific instruments for HRQL assessment are required in the future to reliably evaluate the effects of HMV on HRQL in patients with COPD.